16-Methyl and 16,16 dimethyl PGA{HD 2 {B compounds

ABSTRACT

Prostaglandin E2-type, F2-type, A2-type, and B2-type compounds with one or two methyl or ethyl substituents at the C-16 position are disclosed. These are useful for the same pharmacological purposes as the unsubstituted prostaglandins.

United States Patent [191 Magerlein l6-METHYL AND 16,16 DIMETHYL PGACOMPOUNDS [75] Inventor: Barney J. Magerlein, Portage, Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

[22] Filed: Apr. 23, 1973 [21] Appl. No: 353,475

Related US. Application Data [62] Division of Ser. No. 133,342, April12, 1971,

abandoned.

451 July 1, 1975 [58] Field of Search 260/468 D, 514 D, 514 CA [5 6]References Cited FOREIGN PATENTS OR APPLICATIONS 2,145,600 3/1972Germany 260/468 OTHER PUBLICATIONS Robert, Research in Prostaglandins 2,No. 4, (1973).

Primary Examiner-Robert Gerstl Attorney, Agent, or FirmMorris L. Nielsen[57] ABSTRACT Prostaglandin E -type, F -type, A -type, and B -typecompounds with one or two methyl or ethyl substituents at the C-16position are disclosed. These are useful for the same pharmacologicalpurposes as the unsubstituted prostaglandins.

9 Claims, No Drawings lfi-METHYL AND 16,16 DIMETHYL PGA:

COMPOUNDS This is a division of application Ser. No. 133,342,

filed Apr. 12, 1971, now abandoned.

DESCRlPTlON OF THE INVENTION This invention relates to compositions ofmatter, and to methods and intermediates for producing them. In

particular, the several aspects of this invention relate to 5 glandin E,(PGB Each of the above-mentioned known prostaglandins is a derivative ofprostanoic acid which has the following structure and atom numbering:

A systematic name for prostanoic acid is 7-[(2,8-octyl)-cyclopent-la-yl]heptanoic acid.

PGE has the following structure:

PGF has the following structure:

\ '\./\/\/COOH Ck W PGF has the following structure:

Each of the known prostaglandines PGF PGFM PGFQB. PGA and PGB has astructure the same as that shown for the corresponding PG compoundexcept thatin each, C-5 and C-6 are linked with a cis carbon-carbondouble bond. For example, PGE has the following structure:

The prostaglandin formulas mentioned above each have several centers ofasymmetry. Each formula represents the particular optically active formof the prostaglandin obtained from certain mammalian tissues, forexample, sheep vesicular glands, swine lung, and human seminal plasma,or by reduction or dehydration of a prostaglandin so obtained. See, forexample, Bergstrom et al., Pharmacol. Rev. 20, '1 (1968), and referencescited therein. The mirror image of each formula represents a molecule ofthe enantiomer of that prostaglandin. The racemic form of theprostaglandin consists of equal numbers of two types of molecules, onerepresented by one of the above formulas and the other represented bythe mirror image of that formula. Thus,

both formulas are needed to define a racemic prostaglandin. See Nature212, 38 (1966) for discussion of the stereochemistry of theprostaglandins.

In the formulas above, as well as in the formulas given hereinafter,broken line attachments to the cyclopentane ring indicate substituentsin alpha configuration, i.e., below the plane ofthe cyclopentane ring.See, for example, C-8 and C-1 1 in the PGE formula above. Heavy solidline attachments to the cyclopentane ring indicate substituents in betaconfiguration, i.e., above the plane of the cyclopentane ring. See, forexample, O9 in the PGF formula above. The side-chain hydroxy at C-1 5 inthe formulas above is in alpha configuration.

Each of the novel prostanoic acid analogs of this invention isencompassed by the following formula or by the combination of thatformula and its mirror image:

wherein D is one of the four carbocyclic moieties:

H0 I 0 I 0 wherein indicates attachment of hydroxyl to the cyclopentanering in alpha or beta configuration, wherein R is hydrogen, alkyl of oneto 8 carbon atoms, inclusive, or a pharmacologically acceptable cation,and wherein R and R are hydrogen, methyl, or ethyl, pro- 5 vided that atleast one of R and R is not hydrogen.

Formula I, which is written in generic form for convenience, representsPGE -type compounds when D is PGFza-type compounds when D is PGF -typecompounds when D is PGA -type compounds when D is and PGB -typecompounds when D is 'WOOR: Ill I HO' Each of the novel prostanoic acidanalogs of this invention has one or two methyl or ethyl substituents atC-l6, i.e. the carbon atom adjacent to the hydroxylsubstituted C- 15carbon atom. Thus, these novel prostanoic acid analogs may beconveniently designated l6-methyI-prostaglandins,l-ethyl-prostaglandins, l6- ,16-dimethyl-prostaglandins,16,16-diethylprostaglandins, or 16-methyl-16-ethyl-prostaglandins, e.g.l6-methyl-PGE l6-ethyl-PGF 16,!6- dimethyl-PGF l6,l6-diethyl-PGAl6-methyl-l6- ethyI-PGB and the like.

With regard to Formulas I-VI, examples of alkyl of one to 8 carbonatoms, inclusive, are methyl, ethyl, propyl, butyl, pentyl, hexyl,heptyl, octyl, and isomeric forms thereof.

Like the natural prostaglandins described above, these novel 16- or16,16-di-substituted prostaglandin analogs have several centers ofasymmetry. In addition to those found in the natural prostaglandins,there is an asymmetric center at C-16 when that carbon atom ismono-substituted as in the l6-methyl or l6-ethyl PG compounds.l6-Methyl-PGE therefore, has two C-l6 epimers, both having the sameconfiguration at the other asymmetric centers as that of natural PGEi.e. alpha for the side chain at C-8 and alpha for the hydroxyls at C-11 and C-l5.

As in the case of the formulas representing the prostaglandins, FormulasI through VI are intended to represent optically active prostanoic acidanalogs with the same absolute configuration as PGE obtained frommammalian tissues. The novel prostanoic acid derivatives of thisinvention also include the corresponding racemic compounds. Formula Iplus its mirror image are necessary in combination to describe a racemiccompound. For convenience hereinafter, when the word racemic precedesthe name of one of the novel prostanoic acid derivatives of thisinvention, the intent is to designate a racemic compound represented bythe combination of the appropriate Formula I and the mirror image ofthat formula. When the word racemic does not precede the compound name,the intent is to designate an optically active compound represented onlyby the appropriate Formula I and with the same absolute configuration asPGE obtained from animal tissues.

PGE, and PGE- and the corresponding PGF PGF PGA, and PGE compounds, andtheir esters, and pharmacologically acceptable salts, are extremelypotent in causing various biological responses. For that reason, thesecompounds are useful for pharmacological purposes. See, for example,Bergstrom et al., Pharmacol. Rev. 20, l (1968), and references citedtherein. A few of those biological responses are stimulation of smoothmuscle as shown, for example, by tests on strips of guinea pig ileum,rabbit duodenum, or gerbil colon; potentiation of other smooth musclestimulants; antilipolytic activity as shown by antagonism ofepinephrine-induced mobilization of free fatty acids or inhibition ofthe spontaneous release of glycerol from isolated rat fat pads;inhibition of gastric secretion in the case of the PGE and PGA compoundsas shown in dogs with secretion stimulated by food or histamineinfusion; activity on the central nervous system; decrease of bloodplatelet adhesiveness as shown by platelet-toglass adhesiveness, andinhibition of blood platelet aggregation and thrombus formation inducedby various physical stimuli, e.g., arterial injury, and variousbiochemical stimuli, e.g., ADP, STP, serotonin, thrombin, and collagen;and in the case of the PGE and PGE compounds, stimulation of epidermalproliferation and keratinization as shown when applied in culture toembryonic chick and rat skin segments.

Because of these biological responses, these known prostaglandins areuseful to study, prevent, control, or alleviate a wide variety ofdiseases and undesirable physiological conditions in birds and mammals,including humans, useful domestic animals, pets, and zoologicalspecimens, and in laboratory animals, for example, mice, rats, rabbits,and monkeys.

For example, these compounds and especially the PGE compounds, areuseful in mammals, including man, as nasal decongestants. For thispurpose, the compounds are used in a dose range of about .tg. to about10 mg. per ml. of a pharmacologically suitable liquid vehicle or as anaerosol spray, both for topical application. In this application andthose following, the lower range of dosage is preferred for humans, thehigher range for domestic animals, for example horses or cows.

The PGE and PGA compounds are useful in mammals, including man andcertain useful animals, e.g., dogs and pigs, to reduce the controlexcessive gastric secretion, thereby reducing or avoidinggastrointestinal ulcer formation, and accelerating the healing of suchulcers already present in the gastrointestinal tract. For this purpose,the compounds are injected or infused intravenously, subcutaneously, orintramuscularly in an infusion dose range about 0.1 ,ug. to about 500ug. per kg. of body weight per minute, or in a total daily dose byinjection or infusion in the range about 0.1 to about mg. per kg. ofbody weight per day, the exact dose depending on the age, weight, andcondition of the patient or animal, and on the frequency and route ofadministration.

The PGE, PGFQ, and PGFfl compounds are useful whenever it is desired toinhibit platelet aggregation, to reduce the adhesive character ofplatelets, and to remove or prevent the formation of thrombi in mammals,including man, rabbits, and rats. For example, these compounds areuseful in the treatment and prevention of myocardial infarcts, to treatand prevent post operative thrombosis, to promote patency of vasculargrafts following surgery, and to treat conditions such asatherosclerosis, arteriosclerosis, blood clotting defects due tolipemia, and other clinical conditions in which the underlying etiologyis associated with lipid imbalance or hyperlipidemia. For thesepurposes, these compounds are administered systemically, e.g., intrave'nously, subcutaneously, intramuscularly, and in the form of sterileimplants for prolonged action. For rapid response, especially inemergency situation, the intravenous route of administration ispreferred. Doses in the range about 0.005 to about 20 mg. per kg. ofbody weight per day are used, the exact dose depending on the age,weight, and condition of the patient or animal, and on the frequency androute of administration.

The PGE, PGF and PGF compounds are especially useful as additives toblood, blood products, blood substitutes, and other fluids which areused in artifical extracorporeal circulation and perfusion of isolatedbody portions, e.g., limbs and organs, whether attached to the originalbody, detached and being preserved or prepared for transplant, orattached to a new body. During these circulations and perfusions,aggre-' gated platelets tend to block the blood vessels and portions ofthe circulation apparatus. This blocking is avoided by the presence ofthese compounds. For this purpose, the compound is added gradually or insingle or multiple portions to the circulating blood, to the blood ofthe donor animal, to the perfused body portion, attached or detached, tothe recipient, or to two or all of those at a total steady state dose ofabout 0.001 to 10 mg. per liter of circulating fluid. It is especiallyuseful to use these compounds in laboratory animals, e.g., cats, dogs,rabbits, monkeys, and rats, for these purposes in order to develop newmethods and techniques for organ and limb transplants.

PGE compounds are extremely potent in causing stimulation of smoothmuscle, and are also highly active in potentiating other known smoothmuscle stimulators, for example, oxytocic agents, e.g., oxytocin, andthe various ergot alkaloids including derivatives and analogs thereof.Therefore, PGE for example, is useful in place of or in combination withless than usual amounts of these known smooth muscle stimulators, forexample, to relieve the symptoms of paralytic ileus, or to control orprevent atonic uterine bleeding after abortion or delivery, to aid inexpulsion of the placenta, and during the puerperium. For the latterpurpose, the PGE compound is administered by intravenous infusionimmediately after abortion or delivery at a dose in the range about 0.01to about g. per kg. of body weight per minute until the desired effectis obtained. Subsequent doses are given by intravenous, subcutaneous, orintramuscular injection or infusion during puerperium in the range 0.01to 2 mg. per kg. of body weight per day, the exact dose depending on theage, weight, and condition of the patient or animal.

The PGE, PGF and PGF compounds are useful in place of oxytocin to inducelabor in pregnant female animals, including man, cows, sheep, and pigs,at

l or near term, or in pregnant animals with intrauterine labor, i.e.,expulsion of the fetus. These compounds are especially useful when thefemale is one or more weeks post-mature and natural labor has notstarted, or 12 to 60 hours after the membranes have ruptured and naturallabor has not yet started. An alternative route of administration isoral.

The PGE, PGF and PGF compounds are useful for controlling thereproductive cycle in ovulating female mammals, including humans andanimals such as monkeys, rats, rabbits, dogs, cattle, and the like. Bythe term ovulating female mammals is meant animals which are matureenough to ovulate but not so old that regular ovulation has ceased. Forthat purpose, PGF for example, is administered systematically at doselevel in the range 0.01 mg. to about 20 mg. per kg. of body weight ofthe female mammal, advantageously during a span of time startingapprovimately at the time of ovulation and ending approvimately at thetime of menses or just prior to menses. lntravaginal and intrauterineare alternative route of administration. Additionally, expulsion of anembryo or a fetus is accomplished by similar administration of thecompound during the first third of the normal mammalian gestationperiod.

As mentioned above, the PGE compounds are potent antagonists ofepinephrine-induced mobilization of free fatty acids. For this reason,this compound is useful in experimental medicine for both in vitro andin vivo studies in mammals, including man, rabbits, and rats, intendedto lead to the understanding, prevention, symptom alleviation, and cureof diseases involving abnormal lipid mobilization and high free fattyacid levels, e.g., diabetes mellitus, vascular diseases, andhyperthyroidism.

The PGA compounds and derivatives and salts thereof increase the flow ofblood in the mammalian kidney, thereby increasing volume and electrolytecontent of the urine. For that reason, PGA compounds are useful inmanaging cases of renal disfunction, especially in cases of severelyimpaired renal blood flow, for example, the hepatorenal syndrome andearly kidney transplant rejection. in cases of excessive orinappropriate ADH (antidiuretic hormone; vasopressin) secretion, thediuretic effect of these compounds is even greater. In anephreticstates, the vasopressin action of these compounds is especially useful.lllustratively, the PGA compounds are useful to alleviate and correctcases of edema resulting, for example, from massive surface burns, andin the management of shock. For these purposes, the PGA compounds arepreferably first administered by intravenous injection at a dose in therange 10 to 1000 ug. of body weight or by intravenous infusion at a dosein the range 0.1 to pg. per kg. of body weight per minute until thedesired effect is obtained. Subsequent doses are given by intravenous,intramuscular, or subcutaneous injection or infusion in the range 0.05to 2 mg. per kg. of body weight per day.

The PGE and PGB compounds promote and accelerate the growth of epidermalcells and keratin in animals, including humans, useful domestic animals,pets, zoological specimens, and laboratory animals. For that reason,these compounds are useful to promote and accelerate healing of skinwhich has been damaged, for example, by burns, wounds, and abrasions,and after surgery. These compounds are also useful to promote andaccelerate adherence and growth of skin autografts, especially small,deep (Davis) grafts which are intended to cover skinless areas bysubsequent outward growth rather than initially, and to retard rejectionof homografts.

For these purposes, these compounds are preferably administeredtopically at or near the site where cell growth and keratin formation isdesired, advantageously as an aerosol liquid or micronized powder spray,as an isotonic aqueous solution in the case of wet dressings, or as alotion, cream, or ointment in combination with the usualpharmaceutically acceptable diluents. in some instances, for example,when there is substantial fluid loss as in the case of extensive burnsor skin loss due to other causes, systemic administration isadvantageous, for example, by intravenous injection or infusion,separate or in combination with the usual infusions of blood, plasma, orsubstitutes thereof. Alternative routes of administration aresubcutaneous or intramuscular near the site, oral, sublingual, buccal,rectal, or vaginal. The exact dose depends on such factors as the routeof administration, and the age, weight, and condition of the subject. Toillustrate, a wet dressing for topical application to second and/orthird degree burns of skin area 5 to 25 square centimeters wouldadvantageously involve use of an isotonic aqueous solution containingone to 500 ig/ml. of the PGB compound or several times thatconcentration of the PGE compound. Especially for topical use, theseprostaglandins are useful in combination with antibiotics, for example,gentamycin, neomycin, polymyxin B, bacitracin, spectinomycin, andoxytetracycline, with other antibacterials, for example, mafenidehydrochloride, sulfadiazine, furazolium chloride, and nitrofurazone, andwith corticoid steroids, for example, hydrocortisone, prednisolone,methylprednisolone, and fluprednisolone, each of those being used in thecombination at the usual concentration suitable for its use alone.

The novel Formula-II l6- and l6,l6-di-substituted PGE-type compounds,the novel Formula-HI and -IV PGF -type and PGF -t'ype compounds, thenovel Formula-V PGA-type compounds, and the novel Formula-VI PGB-typecompounds each cause the biological responses described above for thePGE, PGF PGF PGA, and PGB compounds, respectively, and each of thesenovel compounds is accordingly useful for the above-describedcorresponding purposes, and is used for those purposes in the samemanner as described above.

The known PGE, PGF PGF PGA, and PGB compounds uniformly cause multiplebiological responses even at low doses. For example, PGE, and PGE bothcause vasodepression and smooth muscle stimulation at the same time theyexert antilipolytic activity. Moreover, for many applications, theseknown prostaglandins have an inconveniently short duration of biologicalactivity. In striking concontrast, the novel prostaglandin analogs ofFormulas I to VI are substantially more specific with regard to potencyin causing prostaglandin-like biological responses, and have asubstantially longer duration of biological activity. Therefore, each ofthese novel prostaglandin analogs is useful in place of one of thecorresponding above-mentioned known prostaglandins for at least one ofthe pharmacological purposes indicated above for the latter, and issurprisingly and unexpectedly more useful for that purpose because ithas a different and narrower spectrum of biological activity that theknown prostaglandin, and therefore is more specific in its activity andcauses smaller and fewer undesired side effects than the knownprostaglandin. Moreover, becase of its prolonged activity, fewer andsmaller doses of the novel prostaglandin analog can frequently be usedto attain the desired result.

Another advantage of the novel compounds of this invention, especiallythe preferred compounds defined hereinabove, compared with the knownprostaglandins, is that these novel compounds are administeredeffectively orally, sublingually, intravaginally, buccally, or rectally,in addition to usual intravenous, intramuscular, or subcutaneousinjection or infusion methods indicated above for the uses of the knownprostaglandins. These qualities are advantageous because they facilitatemaintaining uniform levels of these compounds in the body with fewer,shorter, or smaller doses, and make possible self-administration by thepatient.

The 16- and l6,l6-di-substituted PGE- PGF PGF PGA- and PGB typecompounds encompassed by Formulas l-VI are used for the purposesdescribed above in the free acid form, in ester form, or inpharmacologically acceptable salt form. When the ester form is used, theester is any of those within the above definition of R However, it ispreferred that the ester be alkyl of one to four carbon atoms,inclusive. Of those alkyl, methyl and ethyl are especially preferred foroptimum absorption of the compound by the body or experimental animalsystem.

Pharmacologically acceptable salts of these Formula- I-Vl I-VI compoundsuseful for the purposes described above are those with pharmacologicallyacceptable metal cations, ammonium, amine cations, or quaternaryammonium cations.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium, sodium, and potassium, and from the alkalineearth metals, e.g., magnesium and calcium, although cationic forms ofother metals, e.g., aluminum, zinc, and iron, are within the scope ofthis invention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary, or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,triisopropylamine, N-methylhexylamine, decyl amine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, a-phenylethylamine, ,Bphenylethylamine,ethylenediamine, diethylenetriamine, and like aliphatic, cycloaliphatic,and araliphatic amines containing up to and including about 18 atoms, aswell as heterocyclic amines, e.g., piperidine, morpholine, pyrrolidine,piperazine, and lower-alkyl derivatives thereof, e.g.,l-methylpiperidine, 4-ethylmorpholine, l-isopropylpyrrolidine,2methylpyrrolidine, 1,4-dimethylpiperazine, Z-methylpiperidine, and thelike, as well as amines containing water-solubilizing or hydrophilicgroups, e.g., mono-, di-, and triethanolamine, ethyldiethanolamine,N-butylethanolamine, 2- amino- 1 -butanol, Z-amino-Z-ethyll,3-propanediol, Z-amine-Z-methyll -propanol, tris( hydroxymethyl-)aminomethane, N-phenylethanolamine, N-(ptertamylphenyl)diethanolamine,galactamine, N- methyl-glucamine, N-methylglycosamine, ephedrine,phenylephrine, epinephrine, procaine, and the like.

Examples of suitable pharmacologically acceptable quaternay ammoniumcations are tetramethylammonium, tetraethylammonium,benzyltrimethylammonium, phenyltriethylammonium, and the like.

As discussed above, the compounds of Formula IVI are administered invarious ways for various purposes;

e.g., intravenously, intramuscularly, subcutaneously, orally,intravaginally, rectally, buccally, sublingually, topically, and in theform of sterile implants for prolonged action.

For intravenous injection or infusion, sterile aqueous isotonicsolutions are preferred. For that purpose, it is preferred because ofincreased water solubility that R in the Formula-I-VI compounds behydrogen or a pharmacologically acceptable cation. For subcutaneous orintramuscular injection, sterile solutions or suspensions of the acid,salt, or ester form in aqueous or nonaqueous media are used. Tablets,capsules, and liquid preparations such as syrups, elixirs, and simplesolutions, with the usual pharmaceutical carriers are used for oralsublingual administration. For rectal or vaginal administration,suppositories prepared as known in the art are used. For tissueimplants, a sterile tablet or silicone rubber capsule or other objectcontaining or impregnated with the substance is used.

The 16- and 16,16-di-substituted PGE PGF PGF PGA and P08 type compoundsencompassed by Formulas l-Vl are produced by the reactions andprocedures described and exemplified hereinafter.

The novel l6-alkyl and 16,16-dialkyl PGE -type acids and esters ofFormula II are prepared by the sequence of transformations shown inCharts and B wherein Formulas VII through XVIII, and II, includeoptically active compounds as shown and racemic compounds of thoseformulas and the mirror image thereof. Also in Charts A and B, R and Rare hydrogen, methyl, or ethyl, provided that at least one of R and R isnot hydrogen; R is (1) wherein T is alkyl of one to 4 carbon atoms,inclusive, phenylalkyl of 7 to 10 carbon atoms, inclusive, or nitro, ands is zero to 5, inclusive, provided that not more than two Ts are otherthan alkyl, and that the total number of carbon atoms in the Ts does notexceed 10 carbon atoms; (2)

wherein R is alkyl of one to 4 carbon atoms, inclusive;

wherein T and s are as defined above; or (4) acetyl; R is hydrogen oralkyl of one to 8 carbon atoms, inclusive; THP is tetrahydropyranyl; andindicates attachment of hydroxyl in alpha or beta configuration. InChart B the novel PGE -type compounds of this invention are encompassedby Formula II.

The various PGF -type and PGF -type compounds encompassed by FormulasIII and IV are prepared by carbonyl reduction of the corresponding PGE-type compounds. For example, carbonyl reduction of l6-methyl-PGE givesa mixture of l6methyl- PGF- and l6-methyl-PGF These ring carbonylreductions are carried out by methods known in the art for ring carbonylreductions of known prostanoic acid derivatives. See, for example,Bergstrom et al., Arkiv Kemi 19, 563 (1963), Acta. Chem. Scand. 16, 969(1962), and British Specification No. 1,097,533. Any reducing agent isused which does not react with carbon-carbon double bonds or estergroups. Preferred reagents are lithium (tri-tertbutoxy)aluminum hydride,the metal borohydrides, especially sodium, potassium and zincborohydrides, and the metal trialkoxy borohydrides, e.g., sodiumtrimethoxyborohydride. The mixtures of alpha and beta hydroxy reductionproducts are separated into the indi vidual alpha and beta isomers bymethods known in the I art for the separation of analogous pairs ofknown isomeric prostanoic acid derivatives. See, for example, Bergstromet al., cited above, Granstrom et al., J. Biol. Chem. 240, 457 (1965),and Green et al., J. Lipid Research 5, 117 (1964). Especially preferredas separation methods are partition chromatographic procedures, bothnormal and reversed phase, preparative thin layer chromatography, andcountercurrent distribution procedures.

The various PGA -type compounds encompassed by Fonnula V are prepared byacidic dehydration of the corresponding PGE type compounds. For example,acidic dehydration of 16-ethyl-PGE gives l6-ethyl- PGA These acidicdehydrations are carried out by methods known in the art for acidicdehydrations of known prostanoic acid derivatives. See, for example,Pike et al., Proc. Nobel Symposium ll, Stockholm (1966), IntersciencePublishers, New York, pp. 162-163 1967); and British Specification1,097,533. Alkanoic acids of 2 to 6 carbon atoms, inclusive, especiallyacetic acid, are preferred acids for this acidic dehydration. Diluteaqueous solutions of mineral acids, e.g., hydrochloric acid, especiallyin the presence of a solubilizing diluent, e.g., tetrahydrofuran, arealso useful as reagents for this acidic dehydration, although thesereagents may cause partial hydrolysis of an ester reactant.

The various l6-alkyl and l6,16-dialkyl PGB -type compounds encompassedby Formula VI are prepared by basic dehydration of the corresponding PGEtype compounds, or by contacting the corresponding PGA type compoundswith base. For example, both 16,16- dimethyl-PGE and 16,16-dimethyl-PGAgive 16,16- dimethyl-PGB on treatment with base.

These basic dehydrations and double bond migrations are carried out bymethods known in the art for similar reactions of known prostanoic acidderivatives. See, for example, Bergstrom et al., J. Biol. Chem. 238,3555 (1963). The base is any whose aqueous solution has pH greater than10. Preferred bases are the alkali metal hydroxides. A mixture of waterand sufficient of a water-miscible alkanol to give a homogeneousreaction mixture is suitable as a reaction medium. The PGE-type orPGA-type compound is maintained in such a reaction medium until nofurther PGB-type compound is formed, as shown by the characteristicultraviolet light absorption near 278 mp. for the PGB type compound.

The various transformations of PGE -type compounds of Formula-ll to thecorresponding Formula-III PGF Formula-IV PGF Formula-V PGA andFormula-VI PGBg type compounds are shown in Chart C, wherein R R R andare as defined above.

Reference to Chart A, herein, will make clear the steps for preparingthe Formula-VII through -XIII intermediates and thence the Formula-XIVbicyclic lactone diol.

Previously, the preparation of an intermediate bicyclic lactone diol ofthe formula was reported by E. J. Corey et al, J. Am. Chem. Soc. 91,5675 1969), and later disclosed in an optically active form by E. J.Corey et al, J. Am. Chem. Soc. 92, 397 (l970). Conversion of thisintermediate to PGE and PGF either in racemic or optically active form,was disclosed in those publications.

The iodolactone of Formula VII in Chart A is known in the art (see Coreyet al, above). It is available in either racemic or optically active orform. For racemic products, the racemic form is used. For prostaglandinsof natural configuration, the laevorotatory form is used.

CHART C' l I l and l V carbonyl reduction R2 CDOR- II S H0 H0 acid R:cooR base w base The Formula-VIII compound (Chart A) bears an R O-moietyat the 4-position, wherein R, is as defined above. In preparing theFormula-VIII compound by replacing the hydrogen of the hydroxyl group inthe 4- position with the acyl group R methods known in the art are used.Thus, an aromatic acid of the formula R OH, wherein R is as definedabove, for example benzoic acid, is reacted with the Formula-VIIcompound in the presence of a dehydrating agent, e.g. sulfuric acid,zinc chloride, or phosphoryl chloride; or an anhydride of the aromaticacid of the formula(R O, for example benzoic anhydride, is used.

Preferably, however, an acyl halide, e.g. R Cl, for example benzoylchloride, is reacted with the Formula- VII compound in the presence of ahydrogen chloridescavenger, e.g. a tertiary amine such as pyridine,triethylamine, and the like. The reaction is carried out under a varietyof conditions using procedures generally known in the art. Generally,mild conditions are employed, e. g. 2060C., contacting the reactants ina liquid medium, e.g. excess pyridine or an inert solvent such asbenzene, toluene or chloroform. The acylating agent is used either instoichiometric amount or in excess.

Wcooa,

/ i I \l/Ry As examples of R the following are available as acids (ROH), anhydrides ((R O), or acyl chlorides (R Cl): benzoyl; substitutedbenzoyl, e.g. (2-, 3- or 4-)- methylbenzoyl, (2-, 3-, or4-)ethylbenzoyl, (2-, 3-, or 4-)isopropylbenzoyl, (2-, 3-, or4-)tert-butylbenzoyl, 2,4-dimethylbenzoyl, 3,5-dimethylbenzoyl, 2-isopropyltoluyl, 2,4,6-trimethylbenzoyl, pentamethylbenzoyl,ocphenyl-(2-, 3-, or 4-)toluyl, 2-, 3-, or 4- )phenethylbenzoyl, 2-, 3-,or 4-nitrobenzoyl, (2,4- 2,5- or 3,5-)-dinitrobenzoyl,3,4-dimethyl-2-nitrobenzoyl, 4,5-dimethyl-2-nitrobenzoyl, 2-nitro-6-phenethylbenzoyl, 3-nitro-2-phenethylbenzoyl; monoesterified phthaloyl,e.g.

or terephthaloyl. e.g.

F. 9 -c- Q-C-o-cne;

(lor 2-)naphthoyl; substituted naphthoyl, e.g. (2-, 3-, 4-, 5-, 6-, or7-)-methyl-1-naphthoyl, (2- or 4-)ethyl-lnaphthoyl,2-isopropyl-l-napthoyl, 4,5-dimethyl-lnaphthoyl,6-isopropyl-4-methyl-l-naphthoyl, S-benzyl-l-naphthoyl, (3-, 4-, 5-, or8-)nitro-l-naphthoyl, 4,5-dinitro-l-naphthoyl, (3-, 4-, 6-, 7-, or8-)methyl-lnaphthoyl, 4-ethyl-2-naphthoyl, and (5- or 8-)nitro-2-naphthoyl; and acetyl. There may be employed, therefore, benzoylchloride, 4-nitroben2oyl chloride, 3,5- dinitrobenzoyl chloride, and thelike, i.e. R Cl compounds corresponding to the above R groups. If theacyl chloride is not available, it is made from the corresponding acidand phosphorus pentachloride as is known in the art. It is preferredthat the R,OH, (R0 0, or R,Cl reactant does not have bulky hinderingsubstituents, e.g. tert-butyl, on both of the ring carbon atoms adjacentto the carbonyl attaching-site.

The Formula-IX compound is next obtained by deiodination of VIII using areagent which does not react with the lactone ring or the OR, moiety,e.g. Zinc dust, sodium hydride, hydrazine-palladium, hydrogen and Raneynickel or platinum, and the like. Especially preferred is tributyltinhydride in benzene at about C. with 2,2-azobis(Z-methylpropionitrile) asinitiator.

The Formula-X compound is obtained by demethylation of IX with a reagentthat does not attack the OR,

moiety, for example boron tribromide or trichloride. The reaction iscarried out preferably in an inert solvent at about O5 C.

The Formula-XI compound is obtained by oxidation of the -CH OH of X to-CHO, avoiding decomposition of the lactone ring. Useful for thispurpose are dichromate-sulfuric acid, Jones reagent, lead tetraacetate,and the like. Especially preferred is Collins reagent (pyridine-CrO atabout Ol0 C.

The Formula-XII compound is obtained by Wittig alkylation of XI, usingthe sodio derivative of dimethyl 2-oxo-3-methylheptylphosphonate. Thetrans enone lactone is obtained stereospecifically see D. H. Wadsworthet al, J. Org. Chem. Vol. 30, p. 680 (1965)).

The Formula-XIII compound is obtained as a mixture of alpha and betaisomers by reduction of XII. For this reduction, use is made of any ofthe known ketonic carbonyl reducing agents which do not reduce ester oracid groups or carbon-carbon double bonds when the latter isundesirable. Examples of those are the metal borohydrides, especiallysodium, potassium, and zinc borohydrides, lithium(tri-tert-butoxy)aluminum hydride, metal trialkoxy borohydrides, e.g.,sodium trimethoxyborohydride, lithium borohydride, diisobutyl aluminumhydride, and when carbon-carbon double bond reduction is not a problem,the boranes, e.g., disiamylborane.

For production of natural-configuration PG-type compounds, the desiredalpha form of the Formula- Xlll compound is separated from the betaisomer by silica gel chromatography.

The Formula-XIV compound is then obtained by deacylation of XIII with analkali metal carbonate, for example potassium carbonate in methanol atabout 25 C. 1

The transformations of the Formula-XIV compounds to the Formula-II PGE--type compounds and the For- 18 mula-III PGF -type compounds are shownin Chart B.

The bis(tetrahydropyranyl) ether XV is obtained by reaction of theFormula-XIV diol with dihydropyran in an inert solvent, e.g.dichloromethane, in the presence of an acid condensing agent such asp-toluenesulfonic acid. The dihydropyran is used in excess, preferably 4to 10 times theory. The reaction is normally complete in 15-30 min. at2030 C.

The lactol XVI is obtained on reduction of the Formula-XV lactonewithout reducing the 13,14-ethylenic group. For this purpose,diisobutylaluminum hydride is prepared. The reduction is preferably doneat 60 to C.

The Formula-XVII compound is obtained by the Wittig reaction, using aWittig reagent derived from 4- carboxy-butyl triphenylphosphoniumbromide and sodio dimethylsulfinylcarbanide, together with theFormula-XVI lactol at about 25 C. This Formula-XVII compound serves asan intermediate for preparing either the PGF -type or the PGE -typeproduct. i The Formula-Ill PGF -type compound is obtained on hydrolysisof the tetrahydropyranyl groups from the Formula-XVII compound, e.g.with methanol/HCI or with acetic acid/water/tetrahydrofuran at 40-55 C.,thereby avoiding formation of PGA -type compounds as by-products.

To prepare the Formula-II PGE -type compounds, thebis(tetrahydropyranyl) ether of PGF (Formula XVII) is oxidized at the9-hydroxy position, preferably with Jones reagent. Finally thetetrahydropyranyl groups are replaced with hydrogen, by hydrolysis as inpreparing the PGF -type product.

When the Wittig reagent for preparing the Formula- XVII compound is acarboxylic acid ester, i.e. the phosphonium halide is of the formulaBr(C I-I P(CH COOR-, wherein R is alkyl of one to 8 carbon atoms,inclusive, the corresponding ester groups are present in the final PGFor PGE -type products.

As discussed above, the processes of Charts B and C, utilizing theintermediates of Chart A, lead either to acids (R is hydrogen) or toalkyl esters (R is alkyl of one to 8 carbon atoms, inclusive). When aFormula l-VI l6-or 16,16-di-substituted PG-type acid has been preparedand an alkyl ester is desired, esterification is advantageouslyaccomplished by interaction of the acid with the appropriatediazohydrocarbon. For example, when diazomethane is used, the methylesters are produced. Similar use of diazoethane, diazobutane, andl-diazo-Z-ethylhexane, for example, gives the ethyl, butyl, and2-ethylhexyl esters, respectively.

Esterification with diazohydrocarbons is carried out by mixing asolution of the diazohydrocarbon in a suitable inert solvent, preferablyethyl ether, with the acid reactant, advantageously in the same or adifferent inert diluent. After the esterification reaction is complete,the solvent is removed by evaporation, and the ester purified if desiredby conventional methods, preferably by chromatography. It is preferredthat contact of the acid reactants with the diazohydrocarbon be no longthan necessary to effect the desired esterification, I

preferably about one to about ten minutes, to avoid undesired molecularchanges. Diazohydrocarbons are known in the art or can be prepared bymethods known in the art. See, for example, Organic Reactions, JohnWiley & Sons, Inc., New York, N.Y., Vol. 8, pp. 389-(1954).

An alternative method for esterification of the carboxyl moiety of thePG-type compounds comprises transformation of the free acid to thecorresponding silver salts, followed by interaction of the salt with analkyl iodide. Examples of suitable iodides are methyl iodide, ethyliodide, butyl iodide, isobutyl iodide, tertbutyl iodide, and the like.The silver salts are prepared by conventional methods, for example, bydissolving the acid in cold dilute aqueous ammonia, evaporating theexcess ammonia at reduced pressure, and then adding the stoichiometricamount of silver nitrate.

The final Formula I-VI compounds prepared by the processes of thisinvention, in free acid form, are transformed to pharmacologicallyacceptable salts by neutralization with appropriate amounts of thecorresponding inorganic or organic base, examples of which correspond tothe cations and amines listed above. These transformations are carriedout by a variety of procedures known in the art to be generally usefulfor the preparation of inorganic, i.e., metal or ammonium, salts, amineacid addition salts, and quaternary ammonium salts. The choice ofprocedure depends in part upon the solubility characteristics of theparticular salt to be prepared. 1n the case of the inorganic salts, itis usually suitable to dissolve the Formula I-VI acid in watercontaining the stoichiometric amount of a hydroxide, carbonate, orbicarbonate corresponding to the inorganic salt desired. For example,such use of sodium hydroxide, sodium carbonate, or sodium bicarbonategives a solution of the sodium salt. Evaporation of the water oraddition of a water-miscible solvent of moderate polarity, for example,a lower alkanol or a lower alkanone, gives the solid inorganic salt ifthat form is desired.

To produce an amine salt, the Formula l-VI acid is dissolved in asuitable solvent of either moderate or low polarity. Examples of theformer are ethanol, acetone, and ethyl acetate. Examples of the latterare ethyl ether and benzene. At least a stoichiometric amount of theamine corresponding to the desired cation is then added to thatsolution. If the resulting salt does not precipitate, it is usuallyobtained in solid form by addition of a miscible diluent of low polarityor by evaporation. If the amine is relatively volatile, any excess caneasily be removed by evaporation. It is preferred to use stoichiometricamounts of the less volatile amines.

Salts wherein the cation is quaternary ammonium are produced by mixingthe Formula I-Vl acid with the stoichiometric amount of thecorresponding quaterna'ry ammonium hydroxide in water solution, followedby evaporation of the water.

Both optically active and racemic 16- and 16,16- disubstituted PG-typecompounds are within the scope of this invention. As disclosed above,racemic intermediates e.g. the racemic Formula-XI aldehyde reacted withracemic Wittig phosphonates lead to racemic products. Optically activeintermediates lead to optically active products. Racemic products areseparated into optically active products if desired, by resolution usingprocedures known in the art. For example, a freeacid Formula I-Vlcompound is resolved by reacting said free acid by known generalprocedures with an optically active base, e.g., brucine or strychnine,to give a mixture of two diastereoisomers which are separated by knowngeneral procedures, e.g., fractional crystallization, to give theseparate diastereoisomeric salts. The optically active acid of Formula Ito V1 is then obtained by treatment of the salt with an acid by knowngeneral procedures.

Those products, racemic or optically active, shown by biologicalscreening tests to have the greatest biological activity are the mostuseful for the purposes described herein. For example, smooth musclestimulation is indicated in smooth muscle strip tests (see J. R. Weekset al., Journal of Applied Physiology 25, (No. 6), 783 (1968); andantisecretory activity is indicated in in vivo tests with laboratoryanimals (see A. Robert, Antisecretory Property of Prostaglandins,Prostaglandin Symposium of the Worcester Foundation for ExperimentalBiology, Interscience, 1968, pp 47-54).

DESCRIPTION OF THE PREFERRED EMBODIMENTS The invention can be more fullyunderstood by the following examples and preparations:

All temperatures are in degrees centigrade.

Infrared absorption spectra are recorded on a Perkin- Elmer model 421infrared spectrophotometer. Except' when specified otherwise, undiluted(neat) samples are used.

NMR spectra are recorded on a Varian A-60 spectrophotometer indeuterochloroform solutions with tetramethylsilane as an internalstandard (downfield).

Mass spectral data are obtained on a Consolidated ElectrodynamicCorporation Model 21-1 10 B High Resolution Mass Spectrometer.

Brine as used herein refers to a saturated aqueous solution of sodiumchloride.

Preparation 1 3a-Benzoyloxy-5a-hydroxy-4-iodo-2B-methoxymethylcyclopentaneacetic Acid y-Lactone (Formula VIII: R, isbenzoyl).

Refer to Chart A. To a mixture of optically active laevorotatoryiodolactone VII (E. J. Corey et al, J. Am. Chem. Soc. Vol. 92, p. 397(1970), g.) in 135 ml. of dry pyridine under a nitrogen atmosphere isadded 30.4 ml. of benzoyl chloride with cooling to maintain thetemperature at about 20-40 C. Stirring is continued for an additional 30min. About 250 ml. of toluene is added and the mixture concentratedunder reduced pressure. The residue is dissolved in one 1. of ethylacetate, washed with 10 percent sulfuric acid, brine, aqueous saturatedsodium bicarbonate, and brine. The ethyl acetate solution is dried oversodium sulfate and concentrated under reduced pressure to yield an oil,g. Crystallization of the oil yields the title compound, m.p. 84-86C.;[a],,+ 7 (CI-ICl infrared spectral absorptions at 1768, 1722, 1600,1570, 1490, 1275, 1265, 1180, 1125, 1090, 1060, 1030, and 710 cm'; andNMR (nuclear magnetic response) peaks at 2.1-3.45, 3.3, 3.58, 4.38,5.12, 5.51, 7.18-7.58, and 7.83-8.05 8.

Following the procedures of Preparation 1, the optically activeFormula-VII iodolactone is transformed to a Formula-VIII compound using,instead of benzoyl chloride, an R Cl reactant wherein R is substitutedbenzoyl, e.g. (2-, 3- or 4-)methylbenzoyl, (2-, 3-, or 4- )ethylbenzoyl,(2-, 3-, or 4-)-isopropylbenzoyl, (2, 3-, or 4-)tertbutylbenzoyl,2,4-dimethylbenzoyl, 3,5- dimethylbenzoyl, 2-isopropyltoluyl, 2,4,6-trimethylbenzoyl, pentamethylbenzoyl, a-phenyl-(2-, 3-, or 4-)toluyl,2-, 3-, or 4-phenethylbenzoyl, 2-, 3-, or 4-nitrobenzoyl, (2,4-, 2,5-,or 3,5-)dinitrobenzoyl, 3,4-dimethyl-2-nitrobenzoyl, 4,5-dimethyl-2-nitrobenzoyl, 2-nitro-6-phenethylbenzoyl, 3-nitro-2- phenethylbenzoyl;mono-esterified phthaloyl, e.g.

isophthaloyl, e.g.

O l C or terephthaloyl, c.g.

(1- or 2-)naphthoyl; substituted naphthoyl, e.g., (2-, 3-, 4-, 5-,6-, or7-)methyl-l-naphthoyl, (2- or 4-)ethyl-lnaphthoyl,2-isopropyl-l-naphthoyl, 4,5-dimethyl-lnaphthoyl,6-isopropyl-4-methyl-l-naphthoyl, 8-benzyl-l-naphthoyl. (3-, 4-, 5- or8-)nitro-l-naphthoyl, 4,5-dinitro-l-naphthoyl, (3-, 4-, 6-, 7- or8-(methyl-lnaphthoyl. 4-ethyl-2-naphthoyl, and (5- or 8-)nitro-2-naphthoyl; and acetyl.

Following the procedures of Preparation 1, but replacing that opticallyactive Formula-VII iodolactone with the racemic compound that formulaand the mirror image thereof, and employing either benzoyl chloride oreach of the R Cl reactants disclosed above, there is obtained thecorresponding racemic Formula-' VIII compound.

Preparation 23a-Benzoyloxy-5a-hydroxy-ZB-methoxy-methylcyclopentaneacetic Acidy-Lactone (Formula IX: R is benzoyl).

Refer to Chart A. To a solution of the optically active Formula-VIIIbenzoxy compound (Preparation 1, 60 g.) in 240 ml. of dry benzene isadded 2,2-azobis-(2- methyl-propionitrile) (approximately 60 mg.). Themixture is cooled to C. and to it is added a solution of 75 g.tributyltin hydride in 600 ml. of ether, with stirring, at such a rateas to maintain continuous reaction at about C. When the reaction iscomplete as shown by TLC (thin layer chromatography) the mixture isconcentrated under reduced pressure to an oil. The oil is mixed with 600ml. of Skellysolve B (isomeric hexanes) and 600 ml. of water and stirredfor min. The. water layer, containing the product, is separated, thencombined with 450 ml. of ethyl acetate and enough solid sodium chlorideto saturate the aqueous phase. The ethyl acetate layer, now containingthe product is separated, dried over magnesium sulfate, and concentratedunder reduced pressure to an oil, 39 g. of the title compound. Ananalytical sample gives [0:1 99 (CHClg); infrared spectra] absorptionsat 1775, 1715, 1600, 1585, 1490, 1315, 1275, 1180, 1110, 1070, 1055,1025, and 715 cm.; NMR peaks at 2.5-3.0, 3.25, 3.34, 4.84-5.17,5.l7-5.4, 7.1-7.5, and 7.8-8.05 8; and mass spectral peaks at 290, 168,105, and 77.

Following the procedures of Preparation 2, each of the optically activeor racemic Formula-VIII compounds following Preparation 1 is transformedto the corresponding optically active or racemic Formula-IX compound.

Preparation 33a-Benzoyloxy-Sa-hydroxy-2B-hydroxy-methylcyclopentaneacetic Acidy-Lactone (Formula X: R, is benzoyl).

Refer to Chart A. To a cold (0-5 C.) solution of lactone IX (Preparation2, 20 g.) in 320 ml. of methylene chloride under nitrogen is added asolution of 24.8 ml. of boron tribromide in320 ml. of dichloromethane,dropwise with vigorous stirring over a period of 50 min. at 0-5 C.Stirring and cooling are continued for 1 hr. When the reaction iscomplete, as shown by TLC, there is cautiously added a solution ofsodium carbonate (78 g. monohydrate) in 200 ml. of water. The mixture isstirred at 0-5 C. for 10-15 min., saturated with sodium chloride, andthe ethyl acetate layer separated. Additional ethyl acetate extractionsof the water layer are combined with the main ethyl acetate solution.The combined solutions are rinsed with brine, dried over sodium sulfateand concentrated under reduced pressure to an oil, 18.1 g. of the titlecompound. An analytical sample has m.p. 116l 18 C.; [a] D 80 (CI-ICIinfrared spectral absorptions at 3460, 1735, 1708, 1600, 1580, 1490,1325, 1315, 1280, 1205, 1115, 1090, 1070, 1035, 1025, 730, and 720; andNMR peaks at 2.1-3.0, 3.58, 4.83-5.12, 5.2-5.45, 7.15-7.55, and 7.8-8.05.

Following the procedures of Preparation 3, each of the optically activeor racemic Formula-IX compounds following Preparation 2 is transformedto the corresponding optically active or racemic Formula-X hydroxymethylcompound.

Preparation 43a-Benzoyloxy-ZB-carboxaldehyde-Sa-hydroxycyclopentaneacetic Acid'y-Lactone (Formula XI: R, is benzoyl).

Refer to Chart A. To a mixture of 150 ml. of dry dichloromethane andCollins reagent (J. C. Collins et al., Tetrahedron Lett. 3363 (1968), 28g.) at about 10 C. under nitrogen is added, with vigorous stirring, acold 10 C.) solution of the optically active hydroxymethyl lactone X(Preparation 3, 5.0 g.) in 150 ml. of dichloromethane. After S-min.additional stirring, about ml. of dry benzene is added, the mixture isfiltered, and the solution is concentrated under reduced pressure. Thevolume is brought to about 150 ml. with benzene. The solution of theFormula-XI title compound is used directly.

From a similar run, there is obtained by concentration of the benzenesolution under reduced pressure an oil which, on trituration with ether,yields crystals of the optically active Formula-XI compound, m.p. C.(dec.); and having NMR peaks at 1.8-3.7, 4.9-5.2, 5.54-5.77, 7.2-7.6,7.7-8.0, and 9.8 6.

Following the procedures of Preparation 4, each of the optically activeor racemic Formula-X hydroxymethyl compounds following preparation 3 istransformed to the corresponding optically active or racemic Formula-XIaldehyde wherein R is one of the R groups listed after Preparation 1,e.g. 2-methylbenzoyl, pentamethylbenzoyl, 2,5-dinitrobenzoyl,monomethylphthaloly, l-naphthoyl, acetyl, and the like.

EXAMPLE 1 Dimethyl 2-Oxo-3-methylheptylphosphonate, a( 2)3' 3) lalan-Butyllithium (150 m1.) is slowly added to a solution of dimethylmethylphosphonate (25.6 g.) in 475 ml. of tetrahydrofuran (THF) at about65 C. To the mixture is added a solution of racemic ethyl 2-methylhexanoate (18.4 g.) in 50 ml. of THF, and the resulting mixture isstirred at 70 C. for 2 hrs. Then, 16 ml. of acetic acid is added, andthe mixture is concentrated under reduced pressure. The residue is mixedwith dichloromethane (about 400 ml.) and water (about 50 ml.), shaken,and separated. The organic phase is dried over magnesium sulfate andconcentrated. Distillation yields the title compound, 16.7 g., b.p.l26-129 C./l mm.

Following the procedures of Example 1 but replacing racemic ethyl2-methylhexanoate with the ethyl esters of the and isomers ofZ-methylhexanoic acid (see P. A. Levene et al., J. Biol. Chem. 70, 211(1926) and 84, 571 (1929)) there are obtained the correspondingoptically active and title compounds.

Likewise following the procedures of Example 1, but replacing ethylZ-methylhexanoate with optically active or racemic ethyl2-ethylhexanoate, there are obtained the corresponding optically activeor racemic phosphonates of the formula CH (CH CH(C H i.e. homologues ofthe title compound wherein the 3- methyl group is replaced by 3-ethyl.

EXAMPLE 2 3 a-Benzoyloxy-S a-hydroxy- 2B( 3-oxo-4-methyl-trans-1-octenyl)-la-cyclopentaneacetic Acid 'y-Lactone (Formula XII; R ishydrogen, R is methyl, and R is benzoyl).

Refer to chart A. A solution of racemic dimethyl 2-oxo-3methylheptylphosphonate (Example 1, 7.9 g.) in 36 m1. of THF isadded, with stirring, to a cold (5 C.) suspension of sodium hydride(55%, 1.62 g.) in 180 ml. of THF. Thereafter the reaction mixture isstirred at about 25 C. for 2.5 hrs., and cooled to l0 C. To the mixtureis added a benzene solution of optically active aldehyde XI (Preparation4, 108 ml.). After 1.5 hrs., 1.8 ml. of acetic acid is added and theTI-IF distilled under vacuum. The residue is dissolved in ethyl acetateand the solution is washed with brine, dried over sodium sulfate, andconcentrated under reduced pressure. Chromatography over silica gelusing 25-30 percent ethyl acetate is Skellysolve B (isomeric hexanes)for elution yields the separated C-l6 epimers of the Formula-XII titlecompound.

Following the procedures of Example 2, using the optically activealdehyde XI, but replacing the racemic phosphonate with each of theoptically active and phosphonates following Example 1, there areobtained the corresponding optically active Formula-XII compounds.

Following the procedures of Example 2, but replacing the aldehyde XIwith each of the optically active or racemic Formula-XI aldehydesdisclosed following Preparation 4, and using either the optically activeor racemic phosphonates of the following Example 1, there are obtainedthe corresponding Formula-XII compound wherein R corresponds to the Rmoiety on the Formula-XI aldehyde. Thus, as in Example 2, the opticallyactive Formula-XII aldehydes, when reacted with a racemic phosphonate,each yield a pair of diastereomers, i.e. l6-epimers of XII, which areseparable by methods known to those skilled in the art, e.g. by silicagel chromatography. The optically active aldehydes, reacted with anoptically active phosphonate, each yield the corresponding opticallyactive compound XII. The racemic Formula-XI aldehydes, when reacted witha racemic phosphonate, each yield two pairs of Formula-XII racemateswhich are separable into separate pairs of racemic compounds by methodsknown in the art, e.g. silica gel chromatography. The racemic aldehydes,reacted with an optically active phosphonate, each yield a pair ofdiastereomers, which are separable, e.g. by silica gel chromatography.

Likewise following the procedures of Example 2, but replacing dimethyl2-oxo-3methylheptylphosphonate with optically active or racemic dimethyl2-oxo-3- ethylheptylphosphonate described following Example 1, andreacting those phosphonates with the optically active or racemicFormula-XI aldehydes disclosed following Preparation 4, there areobtained the corresponding optically active or racemic Formula-XIIcompounds wherein R is hydrogen, R is ethyl, and R is the same as thatR, moiety on the intermediate alde-. hyde.

EXAMPLE 3 3a-Benzoyloxy-5 oz-hydroxy-2B-( 3 a-hydroxy-4-methyltrans-1-octenyl)-la-cyclopentane-acetic Acid 'y-Lactone (FormulaXIII: R is hydrogen, R is methyl, R is benzoyl, and is alpha).

Refer to Chart A. A solution containing the 16- epimers of ketone XII(Example 2, 2.75 g.) in 14 ml. of l,2-di methoxyethane is added to amixture of zinc borohydride prepared from zinc chloride (anhydrous, 4.94g.) and sodium borohydride (1.12 g.) in 48 ml. of dry1,2-dimethoxyethane, with stirring and cooling to l0 C. Stirring iscontinued for 2 hrs. at 0 C., and water (7.8 ml.) is cautiously added,followed by 52 ml. of ethyl acetate. The mixture is filtered, and thefiltrate is separated. The ethyl acetate solution is washed with brine,dried over sodium sulfate, and concentrated under reduced pressure to amixture of the corresponding Formula-XIII l5-alpha and lS-beta isomers.The compounds are subjected to chromatography on a silica gel column,eluting with ethyl acetate, to separate the 15-alpha (less polar) and15-beta isomers of the C-l6 epimers of the Formula-XIII title compounds.

Following the procedures of Example 3, the optically active or racemicFormula-XII ketones derived from the optically active or racemicphosphonates, as described following Example 2, wherein R is benzoyl,are transformed to the corresponding optically active or racemicFormula-XIII hydroxy compounds.

Also following the procedures of Example 3, each of the optically activeor racemic Formula-XII ketones described following Example 2 wherein Ris other than benzoyl is transformed to the corresponding Formula- XIII3'0: and 3'13 hydroxy compounds retaining the R moiety of theFormula-XII ketone,

Likewise following the procedures of Example 3, each of the opticallyactive or racemic 4'-ethyl Formula-XII ketones described followingExample 2 is transformed to the corresponding 4'-ethyl Formula- XIIIhydroxy compounds.

EXAMPLE 4 301,5 a-Dihydroxy-2[3( 3a-hydroxy-4-methyl-transloctenyl)-la-cyclopentaneacetic Acid y-Lactone (Formula XIV: R ishydrogen and R is methyl).

Refer to Chart A. Potassium carbonate (0.79 g.) is added to a solutionof the mixed C-16 alpha and beta epimeric alpha-hydroxy Formula-XIIIcompounds (Example 3, 2.2 g.) in 25 m1 of methanol, and the mixture isstirred for 1 hr. at about 25C. Thereafter, 80 ml. of chloroform isadded, the mixture is filtered, and the organic phase is concentratedunder reduced pressure. The residue is taken up in dichloromethane andthe solution washed with brine. Concentration of the organic phase givesa residue which is triturated with Skellysolve B, then concentrated tothe corresponding mixed C- l 6 alpha and beta epimeric -alpha Formula-XIV title compounds, 1.2 g.

Following the procedures of Example 4, each of the optically active orracemic Formula-XIII hydroxy compounds described following Example 3,wherein R is benzoyl, is transformed to the corresponding opticallyactive or racemic Formula-XIV title compound.

Also following the procedures of Example 4, but replacing thoseFormula-XIII compounds with each of the optically active or racemicFormula-XIII compounds disclosed following Example 3, wherein R is otherthan benzoyl, the said compounds are transformed to the correspondingoptically active or racemic Formula-XIV title compounds.

Likewise following the procedures of Example 4, but employing the4'-ethyl Formula-XIII hydroxy compounds, i.e. wherein R is ethyl, thereare obtained the corresponding optically active or racemic Formula XIVtitle compounds wherein R is hydrogen and R is ethyl.

EXAMPLE 5 3a,5a-Dihydroxy-2B-(3a-hydroxy-4-methyl-trans-1- octenyl la-cyclopentaneacetic Acid 'y-Lactone, 3,3-Bis(tetrahydropyranyl) Ether(Formula XV: R is hydrogen and R is methyl).

Refer to Chart B. A solution of the Formula-XIV diols (Example 4, 1.3g.), 4.25 ml. of dihydropyran, and 0.019 g. of p-toluenesulfonic acid in35 ml. of dichloromethane is stirred at about C. for min. The solutionis washed with potassium bicarbonate solution, dried, and concentratedunder reduced pressure to yield the Formula-XV title compounds, 2.7 g.

Following the procedures of Example 5, each of the optically active orracemic Formula-XIV compounds described following Example 4 istransformed to the corresponding optically active or racemic Formula-XVcompound, e.g. those wherein R is hydrogen and R is either methyl orethyl.

EXAMPLE 6 3a,5a-Dihydroxy-2B-(3a-hydroxy-4-methyl-trans-1- octenyl la-cyclopentaneacetaldehyde 'y-Lactol, 3,3'-Bis(tetrahydropyranyl) Ether(Formula XVI: R is hydrogen, R is methyl, and is alpha or beta).

Refer to Chart B, Diisobutylaluminum hydride (2.6 ml.) in 25 ml. oftoluene is added dropwise to a stirred solution of the Formula- XVtetrahydropyranyl ethers (Example 5, 2.7 g.) in 30 ml. of toluene cooledto -70 C. Stirring is continued at 70 C. for 30 min., whereupon asolution of 12 ml. of THF and 6 ml. of water is cautiously added. Themixture is filtered and the filtrate is washed with brine, dried, andconcentrated to the mixed alpha and beta hydroxy isomers of theFormula-XVI title compounds, 2.4 g., showing no lactone absorption intheir infrared spectra.

Following the procedures of Example 6, each of the optically active orracemic Formula-XV compounds described following Example 5 istransformed to the corresponding optically active or racemic Formula-XVI compound.

EXAMPLE 7 l-Methyl-PGF 1 1,15-Bis(tetrahydropyranyl) Ether (FormulaSVII: R and R are hydrogen, and R is methyl).

Refer to Chart B. 4-Carboxybutyl triphenylphosphonium bromide (5.94 g.)is added to a solution of sodio dimethylsulfinylcarbanide prepared fromsodium hydride (60 percent. 0.90 g.) and 19 ml. of dimethylsulfoxide(DMSO) and the mixture is stirred for 20 min. at about 25 C. To thisreagent is added dropwise the Formula-XVI lactols (Example 6, 2.4 g.) in4 ml. of DMSO. The mixture is stirred at about 25 C. for 16 hrs., thendiluted with about 30 ml. of benzene. To it is added dropwise a solutionof potassium hydrogen sulfate (3.64 g.) in 30 ml. of water, with coolingand stirring. The organic layer is separated, washed with water, dried,and concentrated under reduced pressure. The residue is chromatographedover silica gel using chloroform-methanol (10:1) for elution, to yieldthe Formula-XVII compounds, 1.5 g.

Following the procedures of Example 7, each of the optically active orracemic Formula-XVI compounds described following Example 6 istransformed to the corresponding optically active or racemic Formula-XVII compound.

Likewise following the procedures of Example 7, but replacing4-carboxybutyl triphenylphosphonium bromide with other compounds of theformula Br(C I-I P(CH COOR wherein R is not only hydrogen but also alkylof one to 8 carbon atoms, inclusive, as defined herein, there areobtained the corresponding Formula-XVII compounds wherein R is alkyl ofone to 8 carbon atoms, inclusive.

Example 8 l6-MethyI-PGF (Formula 111: R and R are hydrogen, and R ismethyl).

Refer to Chart B. To a solution of the Formula-XVII bis(tetrahydropyranyl) ethers (Example 7, 0.6 g.) in 5 ml. of THF is added 15.5 ml.of 67% (aqueous) acetic acid. The mixture is warmed to about 55 for 2hrs., then concentrated under 1 mm. pressure. The residue is dissolvedin benzene and chromatographed over silica gel using chloroform-methanol(4:1) for elution. Those fractions shown by thin-layer chromatography(TLC) using the A-IX' system to contain the desired product are combinedand concentrated to yield the Formula-III title compounds, 0.23 g.High-resolution mass spectrum of trimethylsilyl (TMS) derivative: M",656.4135.

Following the procedures of Example 8, each of the optically active orracemic Formula-XVII compounds described following Example 7 istransformed to the corresponding optically active or racemic Formula-IIIcompound. Thus, there are obtained also the corresponding l6-ethyl-PGFcompounds.

EXAMPLE 9 l6-Methyl-PGE- l 1,15-Bis(tetrahydropyranyl) Ether (FormulaXVIII: R and R are hydrogen, and R is methyl).

Refer to Chart B. To a solution of the Formula-XVIIbis(tetrahydropyranyl ether of l6-methyl-PGF (Example 7, 0.9 g.) in 13ml. of acetone at -20 C. is added dropwise 1.0 ml. of Jones reagent (2.1g. of chromic anhydride, 6 ml. of water, and 1.7 ml. of concentratedsulfuric acid). After 15 min. stirring, 1 ml. of 2- propanol is added,with additional stirring, followed by 35 ml. of water. The solution isshaken with three portions of dichloromethane, the organic extracts arecombined, dried, and concentrated under reduced pressure. The residue ischromatographed over silica gel to yield a fraction shown by TLC tocontain the Formula- XVIlI title compounds, 0.5 g.

Following the procedures of Example 9, each of the optically active orracemic Formula-XVII compounds described following Example 7 istransformed to the corresponding optically active or racemic Formula-XVIII compound. There is thus obtained, for example, the1l,15-bis(tetrahydropyranyl) ether of l6-methyl- PGE methyl ester, i.e.Formula XVIII wherein R is hydrogen, and R and R are methyl. Likewise,there is obtained the 1 1,15-bis-(tetrahydropyranyl) ether of16-ethy1-PGE i.e. Formula XVIII wherein R and R are hydrogen, and R isethyl.

EXAMPLE l 16-Methyl-PGE (Formula 11: R and R are hydrogen, and R ismethyl).

Refer to Chart B. A solution prepared from the Formula-XVIII diether(Example 9, 0.5 g.) in 2 ml. of THF and 20 ml. of 67% (aqueous) aceticacid is maintained at 40 C. for 2 hrs. The solvent is removed underreduced pressure, and the residue is chromatographed over silica gelusing chloroform-methanol (:1) for elution. The fractions containing thedesired product as shown by TLC are combined and concentrated to yieldthe Formula-II title compounds, 0.17 g. Highresolution mass spectrum ofTMS derivative: M"- C H 497.2582.

Following the procedures of Example 10, each of the optically active orracemic Formula-XVIII compounds described following Example 9 istransformed to the corresponding optically active or racemic Formula-IIcompounds. There is thus obtained, for example, 16- methyl-PGE methylester, i.e. Formula II wherein R is hydrogen, and R and R are methyl.Likewise, there is obtained 16-ethyl PGE i.e. Formula 11 wherein R and Rare hydrogen, and R is ethyl.

EXAMPLE 1 1 Dimethyl 2-Oxo-3,3-dimethylheptylphosphonate, 3( 2)3- 3)z 11oom-1 1.00%):-

n-Butyllithium (400 ml.) is slowly added to a solution of dimethylmethylphosphonate (73.7 g.) in 1.3 l. of THF at about 66 C. To themixture is added a solution of ethyl 2,2-dimethylhexanoate (53 g.) in150 ml. of THF, and the resulting mixture is stirred at 70 C. for 2 hrs.Then, 46 ml. of acetic acid is added, and the mixture is concentratedunder reduced pressure. The residue is mixed with portions ofdichloromethane (about 1.2 l) and water (about 150 ml.), shaken, andseparated. The organic phase is dried over magnesium sulfate andconcentrated. Distillation yields the title compound, 41.6 g., b.p.l17120 C./1 mm.

Following the procedures of Example 1 1, but replacing ethyl2,2-dimethy1hexanoate, with ethyl 2,2-diethylhexanoate or ethyl2-ethyl-2-methylhexanoate, there are obtained the correspondingphosphonates,

i.e. dimethyl 2-oxo-3,3-diethylheptylphosphonate and dimethyl2-oxo-3-methyl-3-ethylheptylphosphonate.

EXAMPLE l2 3a-Benzoyloxy-5a-hydroxy-2B(3-oxo-4,4-dimethyltransl -octenyll a-cyclopentane-acetic Acid 'y-Lac tone (Formula XII: R and R aremethyl, and R is benzoyl).

Refer to Chart A. A solution of dimethyl 2-oxo-3,3-dimethylheptylphosphonate (Example 11, 11.0 g.) in 50 ml. of THF isadded to a cold (5 C) suspension of sodium hydride (55%, 2.26 g.) in 250ml. of THF, with stirring. Thereafter the reaction mixture is stirred atabout 25 C. for 2.5 hrs., and cooled to l0 C. To the mixture is added abenzene solution of optically active aldehyde XI (Preparation 4, ml.).After 1.5 hrs., 2 ml. of acetic acid is added and the THF distilledunder vacuum. The residue is dissolved in ethyl acetate and the solutionis washed with brine, dried over sodium sulfate, and concentrated underreduced pressure. Chromatography over silica gel using 25-30 percentethyl acetate in Skellysolve B for elution yields the correspondingoptically active title compound, 4.6 g. m.p. 82-3 C.

Following the procedures of Example 12, but replac-, ing the aldehyde XIwith each of the optically active or racemic Formula XI aldehydesdisclosed following Preparation 4 there is obtained the correspondingoptically active or racemic Formula-XII compound wherein R correspondsto the R moiety on the Formula-XI aldehyde.

Likewise following the procedures of Example 12, but replacing dimethyl2-oxo-3,3-dimethylheptylphosphonate with dimethyl2-oxo-3-diethylheptylphosphonate or dimethyl2-oxo-3-ethyl-3-methylheptylphosphonate described following Example 1 1,there is obtained the corresponding optically active or racemicFormula-XII compound wherein R and R are both ethyl or wherein one isethyl and the other is methyl.

EXAMPLE 13 3a-Benzoy1oxy-5 a-hydroxy-2a( 3-hydroxy-4,4-dimethyl-trans-1-octenyl)-l a-cyclopentane-acetic Acid 'y-Lactone(Formula XIII: R and R are methyl, R is benzoyl, ancl is alpha or beta.

Refer to Chart A. A solution of ketone XII (Example 12, 4.65 g.) in 30ml. of 1,2-dimethoxyethane is added to a mixture of zinc borohydrideprepared from zinc chloride (anhydrous, 7.95 g.) and sodium borohydride(1.75 g.) in 71 m1. of dry 1,2-dimethoxyethane, with stirring andcooling to 10 C. Stirring is continued for 2 hrs. at 0 C., and water (12ml.) is cautiously added, followed by 25 ml. of ethyl acetate. Themixture is filtered, and the filtrate is separated. The ethyl acetatesolution is washed with brine, dried over sodium sulfate, andconcentrated under reduced pressure to a mixture of the Formula-XIIIisomers. The alpha and beta isomeric title compounds are separated bychromatography on a silica gel column, eluting with ethyl acetate, toyield 2.1 g. of the alpha isomer and 0.4 g. of the beta isomer,respectively, of the optically active title compounds.

Following the procedures of Example 13, each of the optically active orracemic Formula-XII ketones disclosed following Example 12 istransformed to the corresponding Formula-XIII hydroxy compoundsretaining the R moiety of the Formula-XII ketone. Thus there areobtained Formula-XIII hydroxy compounds wherein R and R are both methylor are both ethyl,

or wherein one is ethyl and the other is methyl.

EXAMPLE l4 3a,5a-Dihydroxy-2B-(3a-hydroxy-4,4-dimethyl-transl-octenyl)-la-cyclopentaneacetic Acid'y-Lactone (Formula XIV: R and R are methyl).

Refer to Chart A. Potassium carbonate (0.72 g.) is added to a solutionof the optically active alpha hydroxy Formula-XIII compound (Example 13,2.1 g.) in 35 ml. of methanol. and the mixture is stirred for 1 hr. atabout 25 C. Thereafter, 75 ml. of chloroform is added, the mixture isfiltered. and the organic phase is concentrated under reduced pressure.The residue is taken up in dichloromethane and the solution washed withbrine. Concentration of the organic phase gives a residue which istriturated with Skellysolve B, then concentrated to the correspondingoptically active Formula-XIV title compound, 1.4 g.

Following the procedures of Example 14, but replacing the Formula-XIIIcompound with each of the optically active or racemic Formula-XIIIcompounds described following Example 3, having R other than ben- Zoyl,there is also obtained the corresponding optically active or racemicFormula XlV title compound. Thus, there are obtained Formula-IVcompounds wherein R and R are both methyl or are both ethyl, or whereinone is ethyl and the other is methyl.

EXAMPLE 15 3a, 5a-Dihydroxy-2B-(3a-hydroxy-4,4-dimethyl-transl-octenyl)-la-cyclopentaneacetic Acid 'y-Lactone, 3,3-Bis(tetrahydropyranyl) Ether(Formula XV: R and R are methyl).

Refer to Chart B. A solution of the optically active Formula-XIV diol(Example 14, 1.4 g.), 4.3 ml. of dihydropyran, and 0.023 g. ofp-toluenesulfonic acid in 30 ml. of dichloromethane is stirred at about25 C. for 30 min. The solution is washed with potassium bicarbonatesolution, dried, and concentrated under reduced pressure to yield thecorresponding optically active Formula-XV title compound, 3.0 g.

Following the procedures of Example 15, the opti cally active or racemicFormula-XIV compounds described following Example 14 are transformed tothe corresponding optically active or racemic Formula-XV compounds.Thus, there are obtained Formula-XV compounds wherein R and R are bothmethyl or are both ethyl, and wherein one is ethyl and the other ismethyl.

EXAMPLE l6 3a,5a-Dihydroxy-2B-( 3a-hydroxy-4,4-dimethyl-transl-octenyl lozcyclopentaneacetaldehyde y-Lactol, 3,3'-Bis(tetrahydropyranyl) Ether(Formula XVI: R and R are methyl, and is alpha or beta).

Refer to Chart B. Diisobutylaluminum hydride (2.5 ml.) in 16 ml. oftoluene is added dropwise to a stirred solution of the optically activeFormula-XV tetrahydropyranyl ether (Example 15, 3.0 g.) in 25 ml. oftoluene cooled to 70 C. Stirring is continued at 70 C. for 30 min.,whereupon a solution of 9 m1. of THF and 4.6 m1. of water is cautiouslyadded. The mixture is filtered and the filtrate is washed with brine,dried, and concentrated to the mixed alpha and beta hydroxy isomers ofthe corresponding optically active Formula- XVI title compound, 2.8 g.,showing no lactone absorption in its infrared spectrum.

Following the procedures of Example 16, the opti' 30 cally active orracemic Formula-XV compounds described following Example 15 aretransformed to the corresponding optically active or racemic'Formula-XVI compounds.

EXAMPLE 17 16,16-Dimethyl-PGF l l, l 5-Bis( tetrahydropyranyl) Ether(Formula XVII: R and R are methyl, and R is hydrogen).

Refer to Chart B. 4-Carboxybutyl triphenylhosphonium bromide (10.5 g.)is added to a solution of sodio dimethylsulfinylcarbanide prepared fromsodium hydride (60%, 2.0 g.) and 50 ml. of DMSO, and the mixture isstirred for 20 min. at about 25 C. To this reagent is added dropwise theoptically active Formula- XVI lactol (Example 16, 2.8 g.) in 9 ml. ofDMSO. The mixture is stirred at about 25 C. for 2 hrs., then dilutedwith about 30 ml. of benzene. To it is added dropwise a solution ofpotassium hydrogen sulfate (6.4 g.) in 30 ml. of water, with cooling andstirring. The organic layer is separated, washed with water, dried, andconcentrated under reduced pressure. The residue is chromatographed oversilica gel using chloroform-methanol 10:1) for elution, to yield thecorresponding optically active Formula-XVII compound, 1.6 g.

Following the procedures of Example 17, the optically active or racemicFormula-XVI compounds described following Example 16 are transformed tothe corresponding optically active or racemic Formula- XVII compounds.

Likewise following the procedures of Example 17, but replacing4-carboxybutyl triphenylphosphonium bromide with other compounds of theformula Br(C H P(CI-I COOR wherein R is not only hydrogen but also alkylof one to 8 carbon atoms, inclusive, as defined herein, there areobtained the corresponding Formula-XVII compounds wherein R, is alkyl ofone to 8 carbon atoms, inclusive.

EXAMPLE l8 16,16-Dimethyl-PGF (Formula III: R and R are methyl, and R ishydrogen).

Refer to Chart B. To a solution of the optically active Formula-XVIIbis(tetrahydropyranyl) ether (Example 17, 0.8 g.) in 5.6 ml. of THF isadded 18.6 ml. of 67% (aqueous) acetic acid. The mixture is warmed toabout 55 for 2 hrs., then concentrated under 1 mm. pressure. The residueis dissolved in benzene and chromatographed over silica gel usingchloroform-methanol (4:1) for elution. Those fractions shown bythin-layer chromatography (TLC) to contain the desired product arecombined and concentrated to yield the corresponding optically activeFormula-III title compound, 0.34 g. High-resolution mass spectrum oftrimethysilyl (TMS) derivative: M -CI-I 655.4047.

Following the procedures of Example 18, the optically active or racemicFormula-XVII compounds described following Example 17 are transformed tothe corresponding optically active or racemic Formula-III compounds.Thus, there are also obtained the corresponding 16,16-diethyl-and16ethyl-16-methy1- PGF compounds.

EXAMPLE l9 l6, 1 6-Dimethyl-PGE l l,l5-Bis(tetrahydropyranyl) Ether(Formula XVIII: R and R are methyl, and R is hydrogen).

Refer to Chart B. To a solution of the optically active Formula-XVIIbis(tetrahydropyranyl) ether of 16,16- dimethyl-PGF (Example 17, 0.8 g.)in 13 ml. of acetone at -20 C. is added dropwise 0.88 ml. of Jonesreagent (2.1 g. of chromic anhydride, 6 ml. of water, and 1.7 ml. ofconcentrated sulfuric acid). After 15 min. stirring, 1 ml. of 2-propanolis added, with additional stirring followed by 35 ml. of water. Thesolution is shaken with three portions of dichloromethane, the organicextracts are combined, dried, and concentrated under reduced pressure.The residue is chromatographed over silica gel to yield a fraction shownby TLC to contain the corresponding optically active Formula-XVIII titlecompound, 0.7 g.

Following the procedures of Example 19, the optically active or racemicFormula-XVII compounds described following Example 18 are transformed tothe corresponding optically active or racemic Formula- XVIII compounds.There are thereby obtained the 16,16-diethyl and l6ethyl-l 6-methyl PGEderivatives of Formula XVIII wherein R and R are both methyl or bothethyl, or wherein one is ethyl and the other is methyl.

EXAMPLE 2O 16,16-Dimethyl-PGE (Formula II: R and R are methyl, and R ishydrogen.

Refer to Chart B. A solution prepared from the optically activeFormula-XVIII diether (Example 19, 0.7 g.) in 5 ml. ofTI-IF and 18 ml.of 67% (aqueous) acetic acid is maintained at 40 C. for 2 hrs. Thesolvent is removed under reduced pressure, and the residue is chrovmatographed over silica gel using chloroform-methanol EXAMPLE 21l6-Methyl-PGF and l6-Methyl-PGF (Formulas III and IV, respectively: Rand R are by rogen, and R is methyl).

Refer to Chart C. A solution of 16-methyl-PGE (Example 10, 300 mg.), 20ml. of tetrahydrofuran, 2.0 ml. of hexamethyldisilazane, and 0.15 ml. oftrimethylsilyl chloride is stirred at 25 for 20 hrs. The reactionmixture is concentrated in vacuo, diluted with benzene, andconcentrated, and this procedure is repeated. The residue is dossolvedin 10 ml. of methanol, cooled in an ice-methanol bath, and to it isadded sodium borohydride (60 mg.) in 20 ml. of cold water dropwise. Themethanol is removed, the aqueous phase is extracted withdichloromethane, and the resulting dichloromethane solution is dried andconcentrated in vacuo. The residue is chromatographed on 45 g. of silicagel using 70 ml. of ethyl acetate and then a gradient of -8 per centmethanol ethyl acetate as eluting solvent, collecting IO-ml. fractions.Fractions shown by TLC to contain the Formula-III title compound, freeof starting materials and by-products, are combined and concentrated toyield the desired Formula-Ill PGF- type title compound. similarly,fractions shown to contain the Formula-IV title compound are combinedand concentrated to yield the desired Formula-IV PGF type titlecompound.

Following the procedure of Example 21, 16,16- dimethyl-PGE (Example 20)is transformed to 16,16- dimethyl-PGF and -PGF Following the proceduresof Example 21, each of the optically active or racemic Formula-II PGE-type compounds described following Examples and is transformed to thecorresponding optically active or racemic Formula-III PGF -type andFormula-IV PGF -type compounds. Thus, there are obtained the opticallyactive or racemic l6-ethyl-, 16,16-diethyland l6-ethyl-l6-methyl-PGF and-PGF type compounds.

EXAMPLE 22 6-Methyl-PGA (Formula V: R and R are hydrogen,v

and R is methyl).

Refer to Chart C. A solution of 16-methyl-PGE (Example 10, 300 mg. 4 ml.of tetrahydrofuran and 4 ml. of 0.5 N hydrochloric acid is left standingat 25 for five days. Brine and dichloromethane-ether 1:3) are added andthe mixture is stirred. The organic layer is separated, dried andconcentrated. The residue is dissolved in ether which is washed withsaturated aqueous sodium bicarbonate, dried and concentrated. Theaqueous phase is quickly acidified with hydrochloric acid and extractedwith dichloromethane which in turn is dried and concentrated.

The residue is again dissolved in ether, extracted with aqueous sodiumbicarbonate, and the aqueous phase is worked up as reported above. Thisprocedure is repeated one additional time to yield the desired Formula-Vtitle compound.

Following the procedure of Example 22, 16,16- dimethyl-PGE (Example 20)is transformed to 16,16- dimethyl-PGA Following the procedures ofExample 22, each of the optically active or racemic Formula-II PGE -typecompounds described following Examples 10 and 20 is transformed to thecorresponding optically active or racemic Formula-V PGA -type compound.Thus, there are obtained the optically active or racemic 16-ethyl-,l6,l6-diethyl-, and 16-ethyl-16-methyl-PGA type compounds.

EXAMPLE 23 l6-Methyl-PGA Methyl Ester (Formula V: R and R are methyl,and R is hydrogen).

A mixture of l6-methyl-PGE methyl ester, (following Example 10, 6 mg.),dicyclohexylcarbodiimide (20mg), copper (II) chloride dihydrate (2 mg.),and diethyl ether (2 ml.) is stirred under nitrogen at 25 C. for 16 hrs.Then, additional dicyclohexylcarbodiimide (20 mg.) is added, and themixture is stirred an additional 32 hrs. at 25 C. under nitrogen. Theresulting mixture is filtered, and the filtrate is evaporated underreduced pressure. The residue is chromatographed by preparative TLC withthe A-IX system to give the desired Formula-V product.

Following the procedure of Example 23, but substituting for the 16-methyl PGE compound, the methyl ester of l6,l6-dimethyl-PGE there isobtained the 33 corresponding Formula-V compound, viz., the methyl esterof 16.16-dimethyl-PGA Also following the procedure of Example 23, butsubstituting for the l6-methyl-PGE compound, the PGE- compounds of andfollowing Examples 10 and 20, there are obtained the correspondingFormula-V PGA -type compounds.

EXAMPLE 24 l-MethylPGB (Formula VI: R and R are hydrogen, and R ismethyl).

Refer to Chart C. A solution of 16-methy1-PGE (Example 10, 200 mg.) in100 ml. of 50 percent aqueous ethanol containing about one gram ofpotassium hydroxide is kept at C. for 10 hrs. under nitrogen. Then, thesolution is cooled to 10 0. and neutralized by addition of 3 N. C. acidat 10 C. The resulting solution is extracted repeatedly with ethylacetate, and the combined ethyl acetate extracts are washed with waterand then with brine, dried, and evaporated to give the desiredFormula-V1 title compound.

Following the procedure of Example 24, lo-methyl- PGA is alsotransformed to the PGB -type title compound.

Following the procedure of Example 24, 16,16- dimethyl-PGE and16,16-dimethyl-PGA are transformed to l6,16-dimethyl-PGB Following theprocedures of Example 24, each of the optically active or racemicFormula-ll PGE- -type compounds described following Examples 10 and 20,and each of the optically active or racemic Formula-V- PGA -typecompounds described following Example 22 is transformed to thecorresponding optically active or racemic Formula-V1 PGB -type compound.Thus, there are obtained the optically active or racemic l6- ethyl-,l6,l6-diethyl-, and 16-ethyl-l6-methyl-PGB type compounds.

EXAMPLE 25 16-Methyl-PGA Methyl Ester (Formula V: R and R are methyl,and R is hydrogen).

A solution of diazomethane (about 50 percent excess) in diethyl ether(25 ml.) is added to a solution of lo-methyhPGA- (Example 22, 50 mg.) in25 ml. of a mixture of methanol and ethyl ether 1:1). The mixture isallowed to stand at 25 C. for 5 min. Then, the mixture is evaporated togive the Formula- V title compound.

Following the procedure of Example 25, each of the other specificl6-methyl or l6,1-dimethyl-substituted PGB -type, PGA -type, GE -type,and PGF -type free acids defined above is converted to the correspondingmethyl ester.

Also following the procedure of Example 25, but using in place of thediazomethane, diazoethane, diazobutane, l-diazo-Z-ethylhexane, anddiazocyclohexane, there are obtained the corresponding ethyl, butyl,Z-ethylhexyl, and cyclohexyl esters of 16-methyl- PGA 1n the samemanner, each of the other specific -methylor methyl-orl6,16-dimethyl-substituted PGB -type, PGA -type, PGE -type, and PGF-type free acids defined above is converted to the corresponding ethyl,butyl, 2-ethylhexyl, and cyclohexyl esters.

EXAMPLE 26 16-Methyl-PGE Sodium Salt.

A solution of lo-methyl-PGE- (Example 10, 100 mg.) in 50 ml. of awater-ethanol mixture (1:1) is cooled to 5 C. and neutralized with anequivalent amount of 0.1 N. aqueous sodium hydroxide solution. Theneutral solution is evaporated to give the title compound.

Following the procedure of Example 26 but using potassium hydroxide,calcium hydroxide, tetramethylammonium hydroxide, andbenzyltrimethylammonium hydroxide in place of sodium hydroxide, thereare obtained the corresponding salts of 16-methyl-PGE Also following theprocedure of Example 26 each of the l6-methyl or16,l6-dimethyl-substituted PGE type, PGF -type, PGA -type, and GB -typeacids defined above is transformed to the sodium, potassium, calcium,tetramethylammonium, and benzyltrimethylammonium salts.

Following the procedures of Example 2, each of the pairs ofdiastereomers, i.e. C- l 6 epimers, of and following Examples 2 through10, inclusive, are separated by methods known in the art, e.g. by silicagel chromatography. Those products shown to have the greatest biologicalactivity by biological screening tests, e.g. smooth muscle strip testsand antisecretory in vivo tests referenced above, are the most usefulfor the purposes described herein.

The solvent systems used in thin layer chromatography herein include:

A 1X Ethyl acetate-acetic acid-2,2,4-trimethylpentane-water(:20:50:100).

A [X Ethyl acetate-acetic acid-Skellysolve B (isomeric hexanes)-water(90:20:50:

See M. Hamberg and B. Samuelsson, J. Biol. Chem. 241, 257 (1966).

I claim:

1. An optically active compound of the formula ,CH (CH2)3COOR1 or aracemic compound of that formula and the mirror image thereof, wherein Ris hydrogen, alkyl of one to 8 carbon atoms, inclusive, or apharmacologically acceptable cation, and wherein R and R are hydrogen,methyl, or ethyl, provided that at least one of R and R is not hydrogen.

2. An optically active compound according to claim 3. A racemic compoundaccording to claim 1.

4. An optically active or racemic compound according to claim 1 whereinR is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or apharmacologically acceptable cation.

5. 16-Methyl-PGA optically active compounds according to claim 1 whereinR and R are hydrogen, and R is methyl.

6. Racemic l6-methyl-PGA compounds according to claim 1 wherein R and Rare hydrogen, and R is methyl.

7. l6,l6-DimethyI-PGA an optically active compound according to claim 1wherein R is hydrogen. and R and R are methyl.

36 cording to claim 1 wherein R, is hydrogen, and R and R are methyl.

1. AN OPTICALLY ACTIVE COMPOUND OF THE FORMULA
 2. An optically activecompound according to claim
 1. 3. A racemic compound according toclaim
 1. 4. An optically active or racemic compound according to claim 1wherein R1 is hydrogen, alkyl of one to 4 carbon atoms, inclusive, or apharmacologically acceptable cation.
 5. 16-Methyl-PGA2, optically activecompounds according to claim 1 wherein R1 and R2 are hydrogen, and R3 ismethyl.
 6. Racemic 16-methyl-PGA2, compounds according to claim 1wherein R1 and R2 are hydrogen, and R3 is methyl. 7.16,16-Dimethyl-PGA2, an optically active compound according to claim 1wherein R1 is hydrogen, and R2 and R3 are methyl. 8.16,16-Dimethyl-PGA2, methyl ester, an optically active compoundaccording to claim 1 wherein R1 and R2, and R3 are methyl.
 9. Racemic16,16-dimethyl-PGA2, a compound according to claim 1 wherein R1 ishydrogen, and R2 and R3 are methyl.